Mutated ras genes have been frequently found in human cancers. For example, these mutated ras genes are found in 90% patients of adenocarcinomas of the pancreas, in 50% of the colon cancer patients, and in 50% of the thyroid tumor patients. The high incidence of mutated ras genes in cancer patients has led many investigators to put their research efforts toward treating mutated ras genes and finding the potential anticancer drugs.
The antibiotic L-azatyrosine, first isolated from Streptomyces chibanesis, has recently been found to possess important antitumor properties (Inouye, S. etc., Chem. Pharm. Bull., 1975, 23, 2669-77) (Monden, Y. etc., Gan to Kagaku Ryoho, 1997, 24, 1563-70). For instance, Shindo-Okada and coworkers reported that L-azatyrosine induces permanent reversion of activated c-Ha-ras-transformed NIH3T3 cells to the apparently normal phenotype, without significantly affecting the growth of cells possessing normal ras gene (Shjindo-Okada, N., etc., Mol. Carcinog., 1989, 2, 159-167) (Krzyzosiak, W. J., etc., Proc. Natl. Acad. Sci., USA, 1992, 89, 4879-83). Studies also proved that L-azatyrosine is involved in the regulation of other oncogenic cell growth. In addition, L-azatyrosine also inhibits 7,12-dimethylbenz[a]anthracene or methylnitrosourea-induced carcinogenesis in mice harboring a normal c-Ha-ras gene (Izawa, M. etc., Cancer Res. 1992, 52, 1628-30). In the same reference, Izawa etc. also demonstrated that L-azatyrosine can block pappilomas induced by a chemical carcinogen at a dose of 2 mg/mouse once every two days for 12 days. Recently, L-azatyrosine was shown to inhibit prostate tumorigenic growth. Incubation with azatyrosine (for 7 days) resulted in greater than 95% in-vitro growth inhibition of three parental prostate cancer cell lines (TSU-Prl, DU-145, and PC-3)(Benoit, R. M. etc., Urology, 1995, 46, 370-377). It also has high reversion efficiency on human prostate cancer cells. These examples have shown that L-azatyrosine plays a potentially significant therapeutic role in the treatment of the advanced prostate cancer.
One drawback of azatyrosine in potential cancer treatment is its low potency. Relatively high concentrations (1-2 mM) are required for the anticancer activity gene (Shjindo-Okada, N., etc., Mol. Carcinog., 1989, 2, 159-167) (Benoit, R. M. etc., Urology, 1995, 46, 370-377). It has been believed that the low rate of transmembrane mechanism by which azatyrosine enters the cell results in the limited efficiency of the compound.
In this invention, a series of N-benzoyl-.alpha.-alkylated azatyrosines as novel derivatives of L-azatyrosine was rationally designed to improve the potency of L-azatyrosine.